Title: Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress
Authors: Hoefkens, Eveline
Nys, Kris
John, Jestinah M
Van Steen, Kristel
Arijs, Ingrid
Van der Goten, Jan
Van Assche, Gert
Agostinis, Patrizia
Rutgeerts, Paul
Vermeire, Severine
Cleynen, Isabelle # ×
Issue Date: Dec-2013
Publisher: Landes Bioscience
Series Title: Autophagy vol:9 issue:12 pages:2046-55
Article number: 10.4161/auto.26337
Abstract: Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings.
ISSN: 1554-8627
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Cell Death Research & Therapy
Translational Research in GastroIntestinal Disorders
× corresponding author
# (joint) last author

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